Obesity is a serious independent risk factor for a number of disorders including diabetes, hypertension and cardiovascular disease. Development of effective measures to treat or prevent obesity will have a significant impact upon the incidence of these other diseases. Obesity is caused by a number of factors. There is a significant genetic component affecting the risk for the development of obesity and environmental factors such as dietary fat content also influence its expression. Interactions of predisposing genes with dietary fat may also be very important in determining the risk for obesity in an individual. The long-term goal of this project is to identify and characterize the genes which predispose for the development of obesity. We propose to use a mouse model initially to identify these genes and then to determine if the same genes or metabolic pathways are controlling the expression of human obesity. The overall approach which we propose to take is the mapping of quantitative trait loci (QTLs) in mouse populations segregating for sensitivity to dietary obesity. In this application, the specific aims are to: A. complete a linkage map of the loci controlling differential sensitivity to dietary obesity in the AKR/J x SWR/J mouse model. B. evaluate the role of specific genetic loci linked to dietary obesity in the AKR/J x SWR/J model in several other genetic models of dietary obesity. C. develop congenic strains for each locus, and several combinations of loci, in order to determine their relative quantitative contribution to the phenotype of dietary obesity. D. evaluate the role of specific candidate genes at these loci.